Bio lab-on-a-chip and method of fabricating and operating the same

ABSTRACT

Disclosed is a bio lab-on-a-chip. The bio lab-on-a-chip is provided on a piezoelectric thin film on a substrate, and includes a sensing unit to sense a bio signal and a fluidic control unit which controls a transfer of a microfluid adjacent to the sensing unit. Provided is also a method of fabricating the bio lab-on-a-chip. The method includes the steps of forming a piezoelectric thin film, forming a sensing unit to sense a bio signal of a microfluid on the piezoelectric thin film, and forming a fluidic control unit located adjacent to the sensing unit.

TECHNICAL FIELD

Hi The present invention relates to a bio-micro electro mechanicalsystem and a method of fabricating the same, and more particularly to abio lab-on-a-chip and methods of fabricating and operating the same.

The present invention has been derived from research undertaken as apart of IT R & D program of the Ministry of Information andCommunication and Institution of Information Technology Association(MIC/IITA) [2006-S-007-02], Ubiquitous health monitoring module andsystem development.

BACKGROUND ART

Generally, in the field of bio-micro electro mechanical systems(Bio-MEMS), to perform processes such as early diagnosis of diseasesand/or chemical analysis on a small chip, a microfluidic control capableof transferring, stopping, mixing, and reacting an ultra-low volumefluid, and an integration of sensors capable of sensing bio markers, forexample, protein, deoxyribonucleic acid (DNA), related to diseases mustbe required.

In the Bio-MEMS field, particularly in the field of chemical analysisand/or early diagnosis of diseases, researches on miniaturization, lowcost, integration, automation, and real-time diagnosis are activelyunder development. Since most of the generic reagents are generallyexpensive, a reproducible and contamination-free chemical analysis mustbe performed using a minimum volume of a bio sample. Accordingly,low-price microfluidic control systems have attracted a specialattention.

However, a conventional microfluidic control system is a mere continuouscontrol system to control a fluid flow by changing a flow rate,preventing a fluid flow and/or causing a reaction by means ofintersecting different fluid flows. In addition, a detection sensor todetect a bio signal of a conventional fluid sample is just a system suchas enzyme-linked immunosorbent assay (ELISA) which uses reactions withina container like a tube, and to utilize reactions in a continuous flowas a fluid form like an electrochemical luminescence, fluorescentluminescence and/or surface plasmon resonance (SPR).

In particular, in order to be used in a chemical analysis and an earlydiagnosis of diseases in a farm of lab-on-a-chip, a microfluidic controlsystem which can transfer, stop, mix, and react a fluid rapidly andexactly while consuming an extremely small volume of a sample, and adetection sensor which can immobilize and sense an antigen like a biomarker must be combined.

So far, to transfer a fluid at a liquid-drop level, a separatemicroactuator has been used as a microfluidic control system to enhanceand stop the fluidic mobility. This type of the microfluidic controlsystem transfers, stops, mixes and reacts a fluid at a liquid-drop levelusing a pressure difference caused by an actuator, for example,piezoelectric, thermopneumatic, and a microfluidic control system andthe actuator are driven individually within the system.

On the contrary, a microfluidic control system has been presented, whichcan transfer, stop, mix, and react a fluid only using the capillaryforce caused in a micro channel and the geometry of the channel withouta separate actuator. Since this type of the microfluidic control systemhas a continuous flow of a fluid consisting of a bio sample, the systemhas the disadvantage that the larger amounts of the bio sample and theexpensive reagents mixed therewith should be consumed to sense a biomarker substantially. The system also has the disadvantage that aseparate device should be required to maintain the dispersion of atarget bio material such as protein, cell, and DNA, in the fluid.

Until now, most of the sensing of bio markers have been performed in acontinuous flow of a fluid. The sensing of bio markers using surfaceacoustic wave (SAW) also follows this pattern. A bio sensor was alsopresented to quantify various analysis materials using a bulk substratemade of quartz. The quartz bulk substrates in the bio sensor aredisadvantageous in that they are expensive and hardly applied to ageneral semiconductor manufacturing process based on typical siliconsubstrates. In addition, when a microfluidic control system and adetection sensor are fabricated on a single chip, peripheral signalprocessing circuits, for example, amplifier circuit, analog/digitalconverter, cannot be integrally formed.

DISCLOSURE OF INVENTION Technical Problem

The present invention provides a bio lab-on-a-chip, which is capable oftransferring, reacting, and sensing a microfluid on a single chip whileminimizing the amount of a sample used.

The present invention also provides a method of fabricating a biolab-on-a-chip capable of transferring, reacting, and sensing amicrofluid on a single chip while minimizing the amount of a sampleused.

The present invention also provides a method of operating a biolab-on-a-chip capable of transferring, reacting, and sensing amicrofluid on a single chip while minimizing the amount of a sampleused.

Technical Solution

Embodiments of the present invention provide bio lab-on-a-chips mayinclude: a substrate; a piezoelectric thin film on the substrate; asensing unit provided on the piezoelectric thin film, and sensing a biosignal of a microfluid; and a fluidic control unit adjacent to thesensing unit, and controlling a transfer of the microfluid.

In some embodiments, the lab-on-a-chip may further include amicrofluidic channel disposed on the piezoelectric thin film between thesensing unit and the fluidic control unit. The microfluidic channel mayinclude a hydrophobic material. The hydrophobic material may include atleast one material selected from a silane compound, a carbon nanotube,and diamond like carbons.

In other embodiments, the substrate may include at least one selectedfrom silicon, glass, plastic, metal, and a combination thereof.

In still other embodiments, the piezoelectric thin film may have athickness in the range of about 0.1 μm to about 10 μm. The piezoelectricthin film may include at least one selected from ZnO, AlN, LiNbO₃,LiTaO₃, quartz, polymer, and a combination thereof.

In even other embodiments, the bio lab-on-a-chip may further includeantibodies provided on the sensing unit. The antibodies may include aself-assembling monolayer (SAM) or protein.

In yet other embodiments, the bio lab-on-a-chip may further include apair of interdigitated transducers disposed adjacent to the sensing unitin a vertical direction to a virtual line connecting the fluidic controlunit and the sensing unit, wherein the sensing unit is positionedbetween the pair of interdigitated transducers.

In further embodiments, the pair of interdigitated transducers mayinclude a selected interdigitated transducer sending a surface acousticwave (SAW) to the sensing unit and an unselected interdigitatedtransducer converting a modulated SAW by the sensing unit into anelectrical signal.

In still further embodiments, the fluidic control unit may be aninterdigitated transducer which provides a SAW in a direction to thesensing unit.

In even further embodiments, the bio lab-on-a-chip may further include adam portion which surrounds the sensing unit and the microfluidicchannel. The dam portion may include a photosensitive polymer.

In other embodiments of the present invention, to solve the othertechnical problems described above, methods for fabricating a biolab-on-a-chip may include: forming a piezoelectric thin film on asubstrate; forming a sensing unit on the piezoelectric thin film, thesensing unit sensing a bio signal of a microfluid: and forming a fluidiccontrol unit adjacent to the sensing unit, the fluidic control unitcontrolling a transfer of the microfluid.

In some embodiments, the piezoelectric thin film may be formed to have athickness in the range of about 0.1 μm to about 10 μm.

In other embodiments, the forming of the piezoelectric thin film mayinclude the steps of depositing a piezoelectric material on thesubstrate and heat-treating the deposited piezoelectric material. Thepiezoelectric material may include at least one selected from ZnO, AlN,LiNbO₃, LiTaO₃, quartz, polymer, and a combination thereof.

In still other embodiments, the depositing of the piezoelectric materialmay include at least one method selected from a reactive sputteringmethod, a chemical vapor deposition (CVD) method, a molecular beamepitaxy method, an atomic layer deposition (ALD) method, and acombination thereof.

In even other embodiments, the fluidic control unit may have a form ofan interdigitated transducer.

In yet other embodiments, the forming of the fluidic control unit may beperformed prior to the forming of the piezoelectric thin film.

In further embodiments, the sensing unit and the fluidic control unitmay be formed simultaneously.

In still further embodiments, the forming of the sensing unit and thefluidic control unit simultaneously may include: forming a photoresistpattern which exposes a sensing unit region and a fluidic control unitregion on the piezoelectric thin film; forming a conductive metal filmon the photoresist pattern and on the piezoelectric thin film exposed bythe photoresist pattern; and removing the photoresist pattern and theconductive metal film on the photoresist pattern by a lift-off process.

In even further embodiments, the forming of a pair of interdigitatedtransducers disposed adjacent to the sensor may be further included in avertical direction to a virtual line connecting the fluidic controllerand the sensor, wherein the sensor is positioned between the pair ofinterdigitated transducers.

In yet further embodiments, the pair of interdigitated transducers maybe formed simultaneously with the fluidic control unit.

In some embodiments, the pair of interdigitated transducers may beformed simultaneously with the sensing unit and the fluidic controlunit.

In other embodiments, the forming of antibodies on the sensing unit maybe further included. The antibodies may include a self-assemblingmonolayer (SAM) or protein.

In still other embodiments, the forming of a dam portion which surroundsthe sensing unit and the microfluidic channel may be further included.The dam portion may be formed of a photosensitive polymer.

In still other embodiments of the present invention, to solve the othertechnical problems described above, methods for operating a biolab-on-a-chip may include: providing a microfluid to a region between asensing unit and a fluidic control unit adjacent to each other on asubstrate having a piezoelectric material; transferring the microfluidto the sensing unit using a surface acoustic wave (SAW) generated bydriving the fluidic control unit; and sensing a bio signal of themicrofluid at the sensing unit.

In some embodiments, the fluidic control unit may be an interdigitatedtransducer for fluid control, which provides the SAW.

In other embodiments, the microfluid may be a liquid drop of nanolitersin volume.

In still other embodiments, the microfluid may include one of an opticalmarker material and a radioactive marker material.

In even other embodiments, the sensing of the bio signal of themicrofluid may include sensing a reaction between antibodies provided onthe sensing unit and the microfluid as an optical signal or aradioactive signal.

In even other embodiments, the sensing of the bio signal of themicrofluid may include sensing a reaction between antibodies provided onthe sensing unit and the microfluid as an electrical signal. The sensingof the electrical signal may use at least one interdigitated transducerdisposed adjacent to the sensing unit, and measure a resonance frequencymodulated as an SAW generated from the interdigitated transducer passesthrough the sensing unit.

In yet other embodiments, a variation of the resonance frequency of theSAW may be proportional to the amount of a reaction between theantibodies and the microfluid.

In further embodiments, the interdigitated transducer may include afirst detection interdigitated transducer sending the SAW to the sensingunit and a second detection interdigitated transducer detecting themodulated SAW at the sensing unit.

In even other embodiments of the present invention, methods foroperating a bio lab-on-a-chip may include: providing a detection sensoron a piezoelectric material, the detection sensor sensing a bio signalof a microfluid; providing a surface acoustic wave (SAW) to thedetection sensor; and measuring a resonance frequency of a modulated SAWby a reaction between the detection sensor and the microfluid, wherein avariation of the resonance frequency of the SAW may be proportional tothe amount of the reaction between the detection sensor and themicrofluid.

In some embodiments, the providing of the SAW may include using at leastone interdigitated transducer adjacent to the detection sensor.

In other embodiments, the interdigitated transducer may include: a firstdetection interdigitated transducer sending the SAW to the detectionsensor; and a second detection interdigitated transducer detecting themodulated SAW at the detection sensor.

ADVANTAGEOUS EFFECTS

As described in detail above, according to the present invention, it ispossible to transfer, stop, react, and sense a microfluid in the form ofa micro-sized drop solution on a single chip. Accordingly, a biolab-on-a-chip may be provided to reduce analysis cost by minimizing theconsumption of a bio sample and reagents. Further, since all theprocesses of a chemical analysis are performed on a single chip, a biolab-on-a-chip may be provided for a rapid and exact analysis. Inaddition, a bio lab-on-a-chip may be provided to reduce fabrication costby replacing an expensive bulk substrate with a piezoelectric thin film.Additionally, a signal-processing unit can be integrated on a singlechip using a general semiconductor manufacturing process. Therefore,this can be also applicable to various bio lab-on-a-chip fields such asa protein lab-on-a-chip, polymerase chain reaction (PCR), DNAlab-on-a-chip and a micro biological/chemical reactor.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures are included to provide a further understandingof the present invention, and are incorporated in and constitute a partof this specification. The drawings illustrate exemplary embodiments ofthe present invention and, together with the description, serve toexplain principles of the present invention. In the figures:

FIG. 1 is a perspective view of a bio lab-on-a-chip according to anembodiment of the present invention;

FIGS. 2 through 5 are conceptual cross-sectional views illustratingreactions in a sensing unit of a bio lab-on-a-chip according to anembodiment of the present invention;

FIG. 6 is a scanning electron microscope image illustrating apiezoelectric thin film of a bio lab-on-a-chip according to anembodiment of the present invention;

FIG. 7 is a graph illustrating a crystalline state of a piezoelectricthin film of a bio lab-on-a-chip according to an embodiment of thepresent inventions;

FIG. 8 is a graph illustrating a resonance characteristic of apiezoelectric thin film of a bio lab-on-a-chip according to anembodiment of the present invention;

FIGS. 9 through 12 are conceptual cross-sectional views illustrating asensing unit of a bio lab-on-a-chip according to an embodiment of thepresent invention;

FIG. 13 is a graph illustrating transitions of a resonance frequency andan amplitude of a bio lab-on-a-chip according to an embodiment of thepresent invention;

FIG. 14 is a graph illustrating a transition degree of a resonancefrequency depending on the amount of antigens of a bio lab-on-a-chipaccording to an embodiment of the present invention;

FIGS. 15 through 24 are cross-sectional views taken along line I-I′ ofFIG. 1, illustrating a method of fabricating a bio lab-on-a-chipaccording to an embodiment of the present invention; and

FIGS. 25 through 31 are cross-sectional views taken along line I-I′ ofFIG. 1, illustrating a method of fabricating a bio lab-on-a-chipaccording to another embodiment of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

Preferred embodiments of the present invention will be described belowin more detail with reference to the accompanying drawings. The presentinvention may, however, be embodied in different forms and should not beconstrued as limited to the embodiments set forth herein. Rather, theseembodiments are provided so that this disclosure will be thorough andcomplete, and will fully convey the scope of the present invention tothose skilled in the art. Additionally, because the reference numeralshave been used to clarify a preferred embodiment, their sequences indescription may not necessarily be limited to a numerical order. In thefigures, the dimensions of layers and regions are exaggerated forclarity of illustration. It will also be understood that when a layer(or film) is referred to as being ‘on’ another layer or substrate, itcan be directly on the other layer or substrate, or intervening layersmay also be present. Further, it will be understood that when a layer isreferred to as being ‘under’ another layer, it can be directly under,and one or more intervening layers may also be present. In addition, itwill also be understood that when a layer is referred to as being‘between’ two layers, it can be the only layer between the two layers,or one or more intervening layers may also be present.

FIG. 1 is a perspective view of a bio lab-on-a-chip according to anembodiment of the present invention.

Referring to FIG. 1, a bio lab-on-a-chip may include a substrate 110, apiezoelectric thin film 114, sensors 122 sa and 122 sb, and fluidiccontrollers 122 ia and 122 ib. The bio lab-on-a-chip may further includea microfluidic channel 126 disposed between the sensors 122 sa and 122sb and the fluidic controllers 122 ia and 122 ib.

The substrate 110 may include at least one selected from silicon (Si),glass, plastic, metal, and a combination thereof. Preferably, thesubstrate 110 may be a silicon substrate.

The piezoelectric thin film 114 may be provided on the substrate 110.The piezoelectric thin film 114 may have a thickness in the range ofabout 0.1 μm to about 10 μm. Preferably, the piezoelectric thin film 114may have a thickness in the range of about 0.5 μm to about 10 μm. Thepiezoelectric thin film 114 may include at least one selected from ZnO,AlN, LiNbO₃, LiTaO₃, quartz, polymer, and a combination thereof.Preferably, the piezoelectric thin film 114 may be a deposited filmhaving a thickness of about 5.5 μm of ZnO.

A silicon oxide (SiO₂) film 112 may be disposed between the substrate110 and the piezoelectric thin film 114. The SiO₂ film 112 may beprovided for minimizing the loss of surface acoustic wave (SAW), whichshould propagate along the piezoelectric thin film 114, by preventingthe SAW from propagating to the substrate 110.

The sensors 122 sa and 122 sb may be provided on the piezoelectric thinfilm 114. The sensors 122 sa and 122 sb may be a conductive metal film.The conductive metal film may include at least one selected from gold(Au), silver (Ag), aluminum (Al), platinum (Pt), tungsten (W), nickel(Ni), copper (Cu), and a combination thereof. Preferably, the sensors122 sa and 122 sb may be an Au-deposited film.

As illustrated in FIG. 1, the sensors 122 sa and 122 sb according to theembodiment of the present invention may include a first sensor 122 saand a second sensor 122 sb. Since a bio lab-on-a-chip includes areference sensor for calibration of the bio lab-on-a-chip and a samplesensor for analysis of bio samples, a pre-calibration may not berequired for the bio lab-on-a-chip. In addition, if the biolab-on-a-chip is pre-calibrated, a simultaneous analysis of two biosamples may be performed.

Antibodies 124 a and 124 b may be further provided on the sensors 122 saand 122 sb.

The antibodies 124 a and 124 b may include a self-assembling monolayer(SAM) or protein. Antigens in microfluids 130 a and 130 b through animmunological reaction such as an antigen-antibody reaction may beadhered to the sensors 122 sa and 122 sb by the antibodies 124 a and 124b.

The fluidic controllers 122 ia and 1221 b may be an interdigitatedtransducer (IDT) which provides the SAW in the direction of the sensors122 sa and 122 sb. The fluidic controllers 122 ia and 122 ib may be aconductive metal film. The conductive metal film may include at leastone selected from Au, Ag, Al, Pt, W, Ni, Cu, and a combination thereof.Preferably, the fluidic controllers 122 ia and 1221 b may be anAu-deposited film the same as the sensors 122 sa and 122 sb.

The microfluidic channel 126 may be provided on the piezoelectric thinfilm 114 between the sensors 122 sa and 122 sb and the fluidiccontrollers 122 ia and 1221 b. The microfluidic channel 126 may includea hydrophobic material. The hydrophobic material may include at leastone selected from a silane compound, a carbon nanotube (CNT), anddiamond like carbon (DLC). Accordingly, the microfluids 130 a and 130 bin the form of a liquid drop may be transferred to the sensors 122 saand 122 sb through the microfluidic channel 126 while maintaining theirforms.

Sensing interdigitated transducers 122 ic and 122 id may be furtherprovided adjacent to the sensors 122 sa and 122 sb in a verticaldirection to a virtual line connecting the fluidic controllers 122 iaand 122 ib to the sensors 122 sa and 122 sb. The sensing interdigitatedtransducers 122 ic and 122 id may be a conductive metal film. Theconductive metal film may include at least one selected from Au, Ag, Al,Pt, W, Ni, Cu, and a combination thereof. Preferably, the sensinginterdigitated transducers 122 ic and 122 id may be an Au-deposited filmthe same as the sensors 122 sa and 122 sb.

The sensing interdigitated transducers 122 ic and 122 id may include apair of interdigitated transducers between which the sensors 122 sa and122 sb may be disposed. The sensing interdigitated transducers 122 icand 122 id may include a first interdigitated transducer for sensingwhich sends the SAW to the sensors 122 sa and 122 sb and a secondinterdigitated transducer for sensing which detects the SAW modulated bythe sensors 122 sa and 122 sb. The first interdigitated transducer andthe second interdigitated transducer may face each other with thesensors 122 sa and 122 sb interposed therebetween. In addition, amicrofluidic channel 127 may be provided on the piezoelectric thin film114 between the sensors 122 sa and 122 sb and the sensing interdigitatedtransducers 122 ic and 122 id. The microfluidic channel 127 may beprovided for easily removing the microfluids 130 a and 130 b which havecompleted reactions with the antibodies 124 a and 124 b in the sensors122 sa and 122 sb, using the SAWs generated from the sensinginterdigitated transducers 122 ic and 122 id.

Since the fluidic controllers 122 ia and 1221 b and the sensinginterdigitated transducers 122 ic and 122 id have a form of aninterdigitated transducer, it may be preferred for them to be formedsimultaneously in the same process. Unlike FIG. 1, the fluidiccontrollers 122 ia and 122 ib and the sensing interdigitated transducers122 ic and 122 id may be provided below the piezoelectric thin film 114.

A dam portion 128 which surrounds the sensors 122 sa and 122 sb and themicrofluidic channels 126 and 127 may be further included. The damportion 128 may include a photosensitive polymer. Accordingly, themicrofluidics 130 a and 130 b in the form of a liquid drop may be stablytransferred to the sensors 122 sa and 122 sb through the microfluidicchannel 126 without deviating outside.

An example of a method of operating a bio lab-on-a-chip in the above maybe as follows.

The microfluids 130 a and 130 b may be provided in the microfluidicchannel 126 between the fluidic controllers 122 ia and 1221 b and thesensors 122 sa and 122 sb disposed adjacent to each other on thesubstrate 110 provided with the piezoelectric thin film 114. Themicrofluids 130 a and 130 b may be liquid drops of nanoliters (nl) involume. The microfluids 130 a and 130 b may also include an opticalmarker material or a radioactive marker material.

The SAW directed to the sensors 122 sa and 122 sb may be produced bydriving the fluidic controllers 122 ia and 122 ib. The microfluids 130 aand 130 b may be moved toward the sensors 122 sa and 122 sb, by the SAWproduced by driving the fluidic controllers 122 ia and 122 ib. If thedriving of the fluidic controllers 122 ia and 122 ib would stop, themicrofluids 130 a and 130 b may be stopped on the sensors 122 sa and 122sb.

The microfluids 130 a and 130 b moved to the sensors 122 sa and 122 sbreact with the antibodies 124 a and 124 b provided on the sensors 122 saand 122 sb. Antigens included in the microfluids 130 a and 130 b maycause an antigen-antibody reaction with the antibodies 124 a and 124 b,and then adhere to the sensors 122 sa and 122 sb.

A bio signal may be sensed from the antigens adhering to the sensors 122sa and 122 sb. The sensing of the bio signal may be to measure anoptical signal or a radioactive signal with respect to the antigensbinding with the optical marker material or the radioactive markermaterial. On the contrary, the sensing of the bio signal may be tomeasure a resonance frequency modulated as the SAW generated from thesensing interdigitated transducers 122 ic and 122 id passes through thesensors 122 sa and 122 sb to which the antigens are adhering. Forexample, as the SAW generated from the first interdigitated transducerpasses through the sensors 122 sa and 122 sb, the resonance frequencythereof may be modulated and detect the modulated SAW in the secondinterdigitated transducer.

Another example of the method of operating a bio lab-on-a-chip as abovemay be as follows.

Each of the microfluidics 130 a and 130 b may be provided in each of themicrofluidic channels 126 disposed between the fluidic controllers 122ia and 122 ib and the sensors 122 sa and 122 sb disposed adjacent toeach other on the substrate 110 with the piezoelectric thin film 114formed. The microfluids 130 a and 130 b may be liquid drops ofnanoliters in volume. The microfluids 130 a and 130 b may also includean optical marker material or a radioactive marker material.

Each of the SAWs directed to the sensors 122 sa and 122 sb may beproduced by driving the fluidic controllers 122 ia and 1221 b. Thefluidic controllers 122 ia and 122 ib may also include a first fluidiccontroller 122 ia and a second fluidic controller 122 ib. Themicrofluids 130 a and 130 b may be moved toward each of the sensors 122sa and 122 sb, by the SAWs produced by driving the fluidic controllers122 ia and 122 ib. The sensors 122 sa and 122 sb may include a firstsensor 122 sa and a second sensor 122 sb. If the driving of the fluidiccontrollers 122 ia and 122 ib would stop, the microfluids 130 a and 130b may be stopped on each of the sensors 122 sa and 122 sb.

The microfluids 130 a and 130 b moved to the sensors 122 sa and 122 sbrespectively may react with a first antibodies 124 a and a secondantibodies 124 b respectively provided on the sensors 122 sa and 122 sb.Each of antigens included in the microfluids 130 a and 130 brespectively may cause an antigen-antibody reaction with each of thefirst antibodies 124 a and the second antibodies 124 b, and then adhereto the sensors 122 sa and 122 sb, respectively.

Each of bio signals may be sensed from each of the antigens adhering toeach of the sensors 122 sa and 122 sb. The sensing of the bio signalsmay be to measure an optical signal or a radioactive signal with respectto each of the antigens binding with the optical marker material or theradioactive marker material. On the contrary, the sensing of the biosignals may be to measure resonance frequencies modulated as the SAWsgenerated from the sensing interdigitated transducers 122 ic and 122 idpasses through the sensors 122 sa and 122 sb to which the antigens areadhering. For example, as the SAWs generated in the first interdigitatedtransducers pass through each of the sensors 122 sa and 122 sb, each ofthe resonance frequencies thereof may be modulated and detect themodulated SAW in the second interdigitated transducers.

The first sensor 122 sa and the second sensor 122 sb may be a standardsensor and a sample sensor, respectively. Since a bio lab-on-a-chipincludes a standard sensor for calibration of the bio lab-on-a-chip anda sample sensor for analysis of bio samples simultaneously, apre-calibration may not be required for the bio lab-on-a-chip. Inaddition, since a background noise of the bio lab-on-a-chip may beremoved by the standard sensor, an exact analysis may be made for thebio sample. The first microfluid 130 a provided to the standard sensor,i.e., the first sensor 122 sa may be a standard sample. Also, amicrofluid may be provided only to the sample sensor, i.e., the secondsensor 122 sb, not to the standard sensor.

In addition, the first sensor 122 sa and the second sensor 122 sb may bea first sample sensor and a second sample sensor, respectively. If a biolab-on-a-chip is pre-calibrated, a simultaneous analysis would bepossible for the two bio samples in the first sample sensor and thesecond sample sensor, respectively.

Since the bio lab-on-a-chip as described above transfer, stop, react,and sense a microfluid as a form of a nanoliter volume drop solutionusing a piezoelectric thin film, all the processes of a chemicalanalysis may be also performed on a single chip while using a minimumvolume of a sample. Accordingly, the costs of analysis may be loweredsimultaneously with the reduced fabricating costs of the biolab-on-a-chip.

FIGS. 2 through 5 are conceptual cross-sectional views illustratingreactions in a sensing unit of a bio lab-on-a-chip according to anembodiment of the present invention.

Referring to FIGS. 2 and 3, antibodies 124 may be provided on a sensor122 s. The antibodies 124 may include a self-assembling monolayer (SAM)or protein.

A microfluid 130 may be transferred to the sensor 122 s by an SAWproduced from a fluidic controller (See 122 ia or 122 ib in FIG. 1). Themicrofluid 130 may be a nanoliter volume liquid drop including variouskinds of antigens 132 a, 132 b and 132 c. The microfluid 130 may alsoinclude an optical marker material or a radioactive marker material.

Referring to FIGS. 4 and 5, only the specific antigens 132 a of themicrofluid 130 may cause an antigen-antibody reaction with and bind tothe antibodies 124. Accordingly, the specific antigens 132 a in themicrofluid 130 may adhere to the sensor 122 s.

A bio signal may be sensed from the antigens 132 a adhering to thesensor 122 s. The sensing of the bio signal may be to measure an opticalsignal or a radioactive signal with respect to the antigens 132 abinding with the optical marker material or the radioactive materialincluded in the microfluid 130. On the contrary, the sensing of the biosignal may be to measure a resonance frequency modulated as the SAWgenerated from the sensing interdigitated transducers (See 122 ic and122 id in FIG. 1) passes through the sensor 122 s to which the specificantigens 132 a are adhering.

The microfluid 130, including the antigens 132 b and 132 c which do notcause the antigen-antibody reaction with the antibodies 124 provided onthe sensor 122 s, may be removed by the SAW produced from the fluidiccontroller and the sensing interdigitated transducers.

FIG. 6 is a scanning electron microscope image illustrating apiezoelectric thin film of a bio lab-on-a-chip according to anembodiment of the present invention, and FIG. 7 is a graph illustratinga crystalline state of a piezoelectric thin film of a bio lab-on-a-chipaccording to an embodiment of the present inventions.

Referring to FIG. 6, an image of a piezoelectric thin film 114 depositedon a substrate 110 was taken using a scanning electron microscope (SEM).The substrate 110 may be a silicon substrate, and the piezoelectric thinfilm 114 may be a film which is heat-treated at about 400° C. under N₂atmosphere for 10 minutes after ZnO is deposited in a thickness of about5.5 μm by a reactive sputtering method. As illustrated in FIG. 6, it isunderstood that a thin film of ZnO may be also grown as a pillar-shapedstructure on a silicon substrate.

Referring to FIG. 7, a graph shows an analysis of the piezoelectric thinfilm 114 on the substrate 110 using X-ray photoelectron spectroscopy(XPS). It is understood that the stoichiometrical atomic compositionratio of zinc to oxygen is 1:1 in a ZnO thin film in a depth directionof the piezoelectric thin film 114. This crystallographical compositionratio is estimated with reference to the value of ZnO in a bulksubstrate.

It is understood that the piezoelectric thin film 114 may be grown wellas a wurtzite structure in the crystal direction (0 0 2) using X-raydiffractometry (XRD) (not shown). In addition, it can be confirmed thatthe grain size of the piezoelectric thin film 114 is about 20 nm throughthe Scherr equation.

As a result, a piezoelectric thin film may be formed on ageneral-purpose silicon substrate, and it was confirmed that thispiezoelectric thin film has a good crystallinity like a bulk substrate.

FIG. 8 is a graph illustrating a resonance characteristic of apiezoelectric thin film of a bio lab-on-a-chip according to anembodiment of the present invention.

Referring to FIG. 8, resulting values of scattering parameters(S-parameters) measured using a vector network analyzer (VNA) areillustrated to know the resonance characteristic of a piezoelectric thinfilm of a bio lab-on-a-chip. The S-parameters are the most widely usedresulting values of circuits in a radio frequency (RF). S11 and S22 inthe S-parameters are the values indicating the ratio of the RF intensityinputted to an input port to the reflected RF intensity outputted fromthe input port, while S12 and S21 are the values indicating the ratio ofthe inputted RF intensity to the input port to outputted RF intensityfrom an output port.

S11 and S22 are the values measured for the reflection characteristicsof a piezoelectric thin film using a pair of interdigitated transducersused as input and output ports. S12 and S21 are the values measured forthe transmission characteristic of the piezoelectric thin film. Asillustrated in FIG. 8, it is understood that a ZnO piezoelectric thinfilm according to embodiments of the present invention has resonancecharacteristics in the specific frequencies of about 175 MHz (Sezawamode) and about 120 MHz (Rayleigh mode).

The resonance is also found to occur in the piezoelectric thin film asin a bulk substrate. Accordingly, transferring, reacting, and sensing ofa microfluid may be performed by the resonance characteristic of thepiezoelectric thin film by a surface acoustic wave (SAW). Thetransferring, reacting, and sensing of the microfluid may be controlledby the sequence of the RF applied to a fluidic controller and/or firstand second sensing interdigitated transducers, and the intensity of theRF energy applied respectively. It could be confirmed that when RFenergy of about 44 V was applied to the fluidic controller as a form ofan interdigitated transducer at about 175 MHz resonance frequency, about200 nl size drop solution propagated at about 20 mm/s.

FIGS. 9 through 12 are conceptual cross-sectional views illustrating asensing unit of a bio lab-on-a-chip according to an embodiment of thepresent invention. It is to describe an immune reaction for analysis ofa prostate-specific antigen (PSA) protein included in a bio sample as anexample.

Referring to FIGS. 9 and 10, cystamines (NH₂—CH₂—CH₂—S—S—CH₂—CH₂—NH) maybe provided on a sensor 122 s in a bio lab-on-a-chip. The sensor 122 smay be an Au-deposited film. A cystamine self-assembling monolayer (SAM)may be formed on the sensor 122 s by the covalent bonds generatedbetween the S atoms included in the cystamines and a surface of thesensor 122 s. Anti-PSA antibodies 124 are provided on the sensor 122 scovered with the cystamine SAM.

Referring to FIGS. 11 and 12, the anti-PSA antibodies 124 may beimmobilized to the sensor 122 s by the covalent bonds generated betweenN atoms included in the cystamines of the cystamine SAM and C atomsincluded in the anti-PSA antibodies. At this time, H atoms binding tothe N atoms included in the cystamines which are covalently bound to theC atoms in the anti-PSA antibodies 124, may be removed and exhaustedduring the covalent bonds.

PSAs 132 are provided on the sensor 122 s immobilized with anti-PSAantibodies 124. Immuno-complexes in which PSAs 132 are binding toanti-PSA antibodies 124 through immune reactions may be formed. Theseimmuno-complexes may be maintained while adhering to the sensor 122 s bythe cystamine SAM.

FIG. 13 is a graph illustrating transitions of a resonance frequency andan amplitude of a bio lab-on-a-chip according to an embodiment of thepresent invention.

Referring to FIG. 13, as anti-PSA antibodies (See 124 in FIG. 10) andPSAs (See 132 in FIG. 11) are sequentially adhering to an Au-depositedsensor (See 122 s in FIG. 9) located between sensing interdigitatedtransducers (See 122 ic and/or 122 id in FIG. 1), the resonancefrequency and the intensity thereof are measured in a graph.

It can be confirmed that as the anti-PSA antibodies and the PSAs aresequentially adhering to the Au-deposited sensor, the resonancefrequency and the intensity thereof become lowered.

FIG. 14 is a graph illustrating a transition degree of a resonancefrequency depending on the amount of antigens of a bio lab-on-a-chipaccording to an embodiment of the present invention.

FIG. 14 illustrates the resonance frequencies depending on the amountsof PSAs reacting with and adhering to anti-PSA antibodies provided on asensor of a bio lab-on-a-chip.

It is understood that as the amounts of the PSAs adhering to the sensorchange in the range from about 2 ng/ml to about 20,000 ng/ml, theresonance frequencies shift. The variation amounts of the resonancefrequency tend to be exponentially proportional to the amounts of thePSAs adhering to the sensor. That is, a quantitative measurement ofantigens adhering to the sensor may be possible.

FIGS. 15 through 24 are cross-sectional views taken along line I-I′ ofFIG. 1, illustrating a method of fabricating a bio lab-on-a-chipaccording to an embodiment of the present invention.

*Referring to FIGS. 15 and 16, a substrate 110 is provided. Thesubstrate 110 may include at least one selected from silicon, glass,plastic, metal, and a combination thereof. Preferably, the substrate 100may be a silicon substrate.

The silicon oxide (SiO₂) film 112 may be formed on the substrate 110.The SiO₂ film 112 may be provided for minimizing the loss of a surfaceacoustic wave (SAW), which should propagate along a piezoelectric thinfilm 114, by preventing the SAW from propagating to the substrate 110.

Referring to FIG. 17, the piezoelectric thin film 114 may be formed onthe SiO₂ film 112. The piezoelectric thin film 114 may be formed to havea thickness in the range of about 0.1 μm to about 10 μm. Preferably, thepiezoelectric thin film 114 may be formed to have a thickness in therange of about 0.5 μm to about 10 μm.

The step of forming the piezoelectric thin film 114 may include the stepof depositing a piezoelectric material on the substrate 110 and the stepof heat-treating the deposited piezoelectric material. The piezoelectricmaterial may include at least one selected from ZnO, AlN, LiNbO₃,LiTaO₃, quartz, polymer, and a combination thereof. The step ofdepositing the piezoelectric material may include at least one methodselected from a reactive sputtering method, a chemical vapor deposition(CVD) method, a molecular beam epitaxy method, an atomic layerdeposition (ALD) method, and a combination thereof. Preferably, thepiezoelectric thin film 114 may be a film which is heat-treated at about400° C. under N₂ atmosphere for about 10 minutes after ZnO is depositedin a thickness of about 5.5 μm by the reactive sputtering method. Thedeposition method for the piezoelectric thin film 114 may be for thedecrease of stresses applied on the deposited piezoelectric material andthe enhancement of the crystallinity of the piezoelectric thin film 114.

Referring to FIG. 18 through 20, a photoresist 116 may be applied on thepiezoelectric thin film 114. A mask pattern 118 may be provided on thephotoresist 116. By performing a photo etching process using the maskpattern 118 as a mask, a photoresist pattern 116 a may be formed toexpose a fluidic controller region A (including a sensing interdigitatedtransducer region) and a sensor region B on the piezoelectric thin film114.

Referring to FIGS. 21 and 22, after the mask pattern 118 is removed, aconductive metal film 120 may be formed on the photoresist pattern 116 aand on the piezoelectric thin film 114 exposed by the photoresistpattern 116 a. The conductive metal film 120 may include at least oneselected from Au, Ag, Al, Pt, W, Ni, Cu, and a combination thereof.

The photoresist pattern 116 a, and the conductive metal film 120 on thephotoresist pattern 116 a may be removed by a lift-off process.Accordingly, a sensor 122 s and a fluidic controller 122 i (including asensing interdigitated transducer) may be formed on the piezoelectricthin film 114. The fluidic controller 122 i may have a form of aninterdigitated transducer.

Referring to FIG. 23, a microfluidic channel 126 may be formed on thepiezoelectric thin film between the sensor 122 s and the fluidiccontroller 122 i. The microfluidic channel 126 may be formed as ahydrophobic material. The hydrophobic material may include at least onematerial selected from a silane compound, a carbon nanotube (CNT), and adiamond like carbon (DLC). Accordingly, a microfluidic in the form of aliquid drop may be transferred to the sensor 122 s through themicrofluidic channel 126 while maintaining its form.

Though not shown, the formation of antibodies (See 124 in FIG. 2) on thesensor 122 s may be further included. The antibodies may include aself-assembling monolayer (SAM) or protein.

Referring to FIG. 24, a dam portion 128 which surrounds the sensor 122 sand the microfluidic channel 126 may be formed. The dam portion 128 maybe formed as a photosensitive polymer. Accordingly, the microfluidic inthe form of a liquid drop may be stably transferred to the sensor 122 sthrough the microfluidic channel 126 without deviating outside.

FIGS. 25 through 31 are cross-sectional views taken along line I-I′ ofFIG. 1, illustrating a method of fabricating a bio lab-on-a-chipaccording to another embodiment of the present invention.

Referring to FIGS. 25 and 26, a substrate 110 is prepared. The substrate110 may include at least one selected from silicon, glass, plastic,metal, and a combination thereof. Preferably, the substrate 110 may be asilicon substrate.

The silicon oxide (SiO₂) film 112 may be formed on the substrate 110.The SiO₂ film 112 may be provided for minimizing the loss of a surfaceacoustic wave (SAW), which should propagate along the piezoelectric thinfilm 114, by preventing the SAW from propagating to the substrate 110.

Referring to FIGS. 27 and 28, a fluidic controller 122 i (including asensing interdigitated transducer) may be formed on the SiO₂ film 112.The fluidic controller 122 i may include at least one selected from Au,Ag, Al, Pt, W, Ni, Cu, and a combination thereof. The fluidic controller122 i may have a form of an interdigitated transducer.

The piezoelectric thin film 114 may be formed to cover the fluidiccontroller 122 i on the SiO₂ film 112. The piezoelectric thin film 114may be formed to have a thickness in the range of about 0.1 μm to about10 μm. Preferably, the piezoelectric thin film 114 may be formed to havea thickness in the range of about 0.5 μm to about 10 μm.

The step of forming the piezoelectric thin film 114 may include the stepof depositing a piezoelectric material on the substrate 110 and the stepof heat-treating the deposited piezoelectric material. The piezoelectricmaterial may include at least one selected from ZnO, AlN, LiNbO₃,LiTaO₃, quartz, polymer, and a combination thereof. The step ofdepositing the piezoelectric material may include at least one methodselected from a reactive sputtering method, a CVD method, a molecularbeam epitaxy method, an atomic layer deposition (ALD) method, and acombination thereof. Preferably, the piezoelectric thin film 114 may bea film which is heat-treated at about 400° C. under N₂ atmosphere forabout 10 minutes after ZnO is deposited in a thickness of about 5.5 μmby the reactive sputtering method. The deposition method for thepiezoelectric thin film 114 may be for the decrease of stresses appliedon the deposited piezoelectric material and the enhancement of thecrystallinity of the piezoelectric thin film 114.

Referring to FIG. 29, a sensor 122 s may be formed on the piezoelectricthin film 114. The sensor 122 s may include at least one selected fromAu, Ag, Al, Pt, W, Ni, Cu, and a combination thereof.

Though not shown, the formation of antibodies (See 124 in FIG. 2) on thesensor 122 s may be further included. The antibodies may include aself-assembling monolayer (SAM) or protein.

Referring to FIG. 30, a microfluidic channel 126 may be formed on thepiezoelectric thin film 114 between the sensor 122 s and the fluidiccontroller 122 i. The microfluidic channel 126 may be formed as ahydrophobic material. The hydrophobic material may include at least onematerial selected from a silane compound, a carbon nanotube (CNT), and adiamond like carbon (DLC). Accordingly, a microfluid in the form of aliquid drop may be transferred to the sensor 122 s through themicrofluidic channel 126 while maintaining its form.

Referring to FIG. 31, a dam portion 128 which surrounds the sensor 122 sand the microfluidic channel 126 may be formed. The dam portion 128 maybe formed as a photosensitive polymer. Accordingly, the microfluid inthe form of a liquid drop may be stably transferred to the sensor 122 sthrough the microfluidic channel 126.

Since a bio lab-on-a-chip according to the methods of fabricating thesame described above may perform transferring, stopping, reacting, andsensing of a microfluid in the form of a nanoliter volume drop solution,all the processes of the chemical analysis may be performed on a singlechip while using the minimum volume of a sample. Accordingly, the costsof analysis may be lowered simultaneously with the reduced fabricatingcosts of a bio lab-on-a-chip.

Since a bio lab-on-a-chip according to embodiments of the presentinvention described above may perform transferring, stopping, reacting,and sensing of a microfluid in the form of a nanoliter volume dropsolution, the minimization of the consumption of a bio sample andreagents may be achieved. Accordingly, the costs of analysis may belowered. Further, since all the processes of the chemical analysis areperformed on a single chip, a rapid and exact analysis may be made. Inaddition, the reduction of the fabricating costs by replacing anexpensive bulk substrate with a piezoelectric thin film. Additionally,since the present invention may be applied to a multi-use semiconductormanufacturing process, it may be applicable to various bio lab-on-a-chipfields including a protein lab-on-a-chip, a polymerase chain reaction(PCR) chip, deoxyribonucleic acid (DNA) lab-on-a-chip or a microbiological/chemical reactor.

INDUSTRIAL APPLICABILITY

The present invention may apply to a bio-micro electronic mechanicalsystems (bio-MEMS) for chemical analysis of bio samples andinstrumentation of bio signals.

1. A bio lab-on-a-chip comprising: a substrate; a piezoelectric thinfilm on the substrate; a sensing unit provided on the piezoelectric thinfilm, and sensing a bio signal of a microfluid; and a fluidic controlunit adjacent to the sensing unit, and controlling a transfer of themicrofluid.
 2. The bio lab-on-a-chip of claim 1, further comprising amicrofluidic channel disposed on the piezoelectric thin film between thesensing unit and the fluidic control unit.
 3. The bio lab-on-a-chip ofclaim 2, wherein the microfluidic channel comprises a hydrophobicmaterial.
 4. (canceled)
 5. The bio lab-on-a-chip of claim 1, wherein thesubstrate comprises at least one selected from silicon, glass, plastic,metal, and a combination thereof.
 6. The bio lab-on-a-chip of claim 1,wherein the piezoelectric thin film has a thickness in the range ofabout 0.1 μm to about 10 μm.
 7. (canceled)
 8. The bio lab-on-a-chip ofclaim 1, further comprising antibodies provided on the sensing unit. 9.The bio lab-on-a-chip of claim 8, wherein the antibodies comprise aself-assembling monolayer (SAM) or protein.
 10. The bio lab-on-a-chip ofclaim 1, further comprising a pair of interdigitated transducersdisposed adjacent to the sensing unit in a vertical direction to avirtual line connecting the fluidic control unit and the sensing unit,wherein the sensing unit is positioned between the pair ofinterdigitated transducers.
 11. The bio lab-on-a-chip of claim 10,wherein the pair of interdigitated transducers comprise: a selectedinterdigitated transducer sending a surface acoustic wave (SAW) to thesensing unit; and an unselected interdigitated transducer converting amodulated SAW by the sensing unit into an electrical signal.
 12. The biolab-on-a-chip of claim 1, wherein the fluidic control unit is aninterdigitated transducer which provides a SAW in a direction to thesensing unit.
 13. The bio lab-on-a-chip of claim 1, further comprising adam portion which surrounds the sensing unit and the microfluidicchannel. 14-30. (canceled)
 31. A method of operating a biolab-on-a-chip, the method comprising: providing a microfluid to a regionbetween a sensing unit and a fluidic control unit adjacent to each otheron a substrate having a piezoelectric material; transferring themicrofluid to the sensing unit using a surface acoustic wave (SAW)generated by driving the fluidic control unit; and sensing a bio signalof the microfluid at the sensing unit.
 32. The method of claim 31,wherein the fluidic control unit is an interdigitated transducer forfluid control, which provides the SAW.
 33. The method of claim 31,wherein the microfluid is a liquid drop of nanoliters in volume.
 34. Themethod of claim 31, wherein the microfluid comprises one of an opticalmarker material and a radioactive marker material.
 35. The method ofclaim 31, wherein the sensing of the bio signal of the microfluidcomprises sensing a reaction between antibodies provided on the sensingunit and the microfluid as an optical signal or a radioactive signal.36. The method of claim 31, wherein the sensing of the bio signal of themicrofluid comprises sensing a reaction between antibodies provided onthe sensing unit and the microfluid as an electrical signal.
 37. Themethod of claim 36, wherein the sensing of the electrical signal uses atleast one interdigitated transducer disposed adjacent to the sensingunit, and measures a resonance frequency modulated as an SAW generatedfrom the interdigitated transducer passes through the sensing unit. 38.The method of claim 37, wherein a variation of the resonance frequencyof the SAW may be proportional to the amount of a reaction between theantibodies and the microfluid.
 39. The method of claim 37, wherein theinterdigitated transducer comprises: a first detection interdigitatedtransducer sending the SAW to the sensing unit; and a second detectioninterdigitated transducer detecting the modulated SAW at the sensingunit. 40-42. (canceled)